Intermediates for synthesis of cephalosporins and process for preparation of such intermediates

ABSTRACT

A novel 4-halo-2-oxyimino-3-oxo butyric acid-N,N-dimethyl formiminium chloride chlorosulfate of formula (I) useful in the preparation of cephalosporin antibiotics 
                         
wherein
 
     X is chlorine or bromine; R is hydrogen, C 1-4  alkyl group, an easily removable hydroxyl protective group, —CH 2 COOR 5 , or —C(CH 3 ) 2 COOR 5 , wherein R 5  is hydrogen or an easily hydrolysable ester group. The compound of formula (I) is prepared by reacting 4-halo-2-oxyimino-3-oxobutyric acid of formula (IV 1 ), 
                         
wherein X, R and R 5  are as defined above, with N,N-dimethylformiminium chloride chlorosulphate of formula (VII)
 
                         
in an organic solvent at a temperature ranging from −30° C. to −15° C. The cephalosporins that may be prepared from the intermediate include cefdinir, cefditoren pivoxil, cefepime, cefetamet pivoxil, cefixime, cefmenoxime, cefodizime, cefoselis, cefotaxime, cefpirome, cefpodoxime proxetil, cefquinome, ceftazidime, cefteram pivoxil, ceftiofur, ceftizoxime, ceftriaxone and cefuzonam.

FIELD OF THE INVENTION

The present invention relates to novel compounds of formula (I),

wherein X is chlorine or bromine; R is hydrogen, C₁₋₄ alkyl group, aneasily removable hydroxyl protective group, —CH₂COOR₅, or —C(CH₃)₂COOR₅,wherein R₅ is hydrogen, or an easily hydrolysable ester group. Thepresent invention also relates to a process for preparation of thecompounds of formula (I). The invention also relates to the use of thenovel compounds of formula (I) for preparation of cephalosporinantibiotics, in particular cephalosporin compounds of formula (II).

wherein R and R₅ are as defined above; R₁ is hydrogen or —OCH₃; R₂ ishydrogen; R₃ is hydrogen, a negative charge or together with the COO⁻group to which R₃ is attached is an ester, or an alkali or alkalineearth metal; R₄ is hydrogen or is a substituent useful in cephalosporinchemistry.

BACKGROUND OF THE INVENTION

Cephalosporin compounds of formula (II) are generally synthesised by twomethods as described in the art. Both the methods involve amidificationof the 7-amino function of the corresponding 3-(un)substitutedcephalosporin derivative either directly with a 2-(2-aminothiazol-4-yl)-2-oxyimino acetic acid derivative (Method-I) or viaMethod-II a 4-halo-2-oxyimino-butyric acid derivative to give a7-substituted cephalosporin addendum, which can be further elaborated toform the 2-(2-amino thiazol-4-yl)-2-oxyimino acetamido side chain andthereby, provide compounds of formula (II). The two methods of synthesisare summarized in Scheme-I.

In compounds of formula (III) of Method-I, the meanings of the groups Xand R are as defined hereinearlier and the group Y is hydrogen or is agroup which forms a basis that compound of formula (III) is in areactive form. Similarly, in compound of formula (IV), of Method-II, themeanings of the groups X and R are as defined hereinearlier and thegroup Z is hydrogen or is a group which forms a basis that compound offormula (IV) is in a reactive form.

As per Method-I, synthesis of compound of formula (II) has been achievedby several ways, all differing in the choice of the reactive group Y.The following prior art methods illustrate the synthesis of compounds offormula (II) utilizing different reactive species as embodied in thegroup Y. These are to name a few;

-   i) U.S. Pat. No. 4,152,432 describes synthesis of cefotaxime    comprising acylation of 7-aminocephalosporanic acid (7-ACA) with a    compound of formula (III), wherein R is methyl and Y is a chlorine    atom. In this method, the amino group of the thiazole ring is    protected prior to amidification and subsequently deprotected by    hydrolysis or hydrogenolysis.    -   Japanese Patent Nos. JP 52-102096, JP 53-157596 and British        Patent No. GB 2 025 933 also utilize the same chemistry        mentioned hereinbefore i. e. activation of the carboxylic acid        as the acid halide. The acid halide, in particular the acid        chloride is prepared by reaction of the 2-(2-amino        thiazol-4-yl)-2-oxyimino acetic acid with PCl₃, PCl₅, SOCl₂ or        POCl₃.    -   U.S. Pat. No. 3,954,745 also teaches a method for synthesis of        cefazolin via the acid chloride method.-   ii) Another method of activation of the carboxylic acid of formula    (III), as disclosed in U.S. Pat. No. 5,317,099 is through formation    of the activated ester by reaction of the carboxylic acid group with    an acyloxyphosphonium chloride derivative. The method of preparation    comprises reacting the carboxylic acid derivative (III) with    triphenyl phosphine, hexachloroethane or carbon tetrachloride.    However, this method increases the overall cost of the coupling    reaction since it involves the use of expensive triphenyl phosphine.-   iii) EP Patent Nos. EP 0 037 380 describes yet another method for    synthesis of compounds of formula (II), specially cefotaxime and    ceftriaxone, wherein the carboxylic acid group of compound (III) is    activated as the benzothiazolyl thioester prior to formation of the    amide bond at the 7-amino position. The benzothiazolyl thioester is    turn prepared by reaction of the carboxylic acid compound (III) with    bis[benzothiazolyl-(2)]disulfide and triphenyl phosphine, thereby    rendering the method costly.-   iv) U.S. Pat. No. 5,037,988 describes a process for production of    compounds of formula (II), in particular, cefotaxime and    ceftriaxone, in which the 2-(2-amino thiazol-4-yl)-2-oxyimino acetic    acid (III) is activated as the dimethyl formiminium chloride    chlorosulfite (DFCS) of formula (VI) and then coupled at the 7-amino    position of the 3-substituted cephalosporin derivative to give    compounds of formula (II).

-   -   The dimethyl formiminium chloride chlorosulfite (VI), is in turn        prepared by reacting equimnolar quantities of thionyl chloride        and N,N-dimethylformamide at room temperature. The method        however, suffers from drawbacks inter alia in that the reaction        can be effected in only specific solvents like benzene and        toluene.

-   v) U.S. Pat. No. 5,739,346 describes a process for synthesis of    β-lactam derivatives such as cefotaxime and ceftriaxone wherein    compound (III) is activated as an adduct with N,N dimethyl    formiminium chloride chlorosulfite (DFCCS) of formula (VII), prior    to 7-amidification to give compounds of formula (II).

-   vi) WO 99/51607 discloses a process for preparation of cefixime,    wherein 7-amino-3-vinyl-3-cephem-4-carboxylic acid is reacted with    compound (III) activated as the benzothiazolyl thioester.-   vi) U.S. Pat. No. 6,388,070 provides yet another variation, wherein    the compound (III) is activated as a    2-mercapto-5-substituted-1,3,4-oxadiazole derivative prior to    7-amidification to give compounds of formula (II).

The amidification has also been achieved by activation of the carboxylicacid (III) by formation of its mixed anhydride, an active amide or anactive ester, as disclosed in U.S. Pat. No. 4,409,214; as thethiophosphoryl ester, as disclosed in U.S. Pat. No. 5,567,813 forsynthesis of cefixime, cefotaxime, ceftriaxone, cefepime, cefpiromesulfate, ceftizoxime etc.

Synthesis of compounds of formula (II) as per Method-II is equallywidely documented in the literature. Several methods, varying subtly inthe choice of the reactive group Z of compounds of formula (IV) havebeen utilised, albeit the choice of the activating group is primarilyrestricted to acid halides. A few of such methods are disclosed in:

-   a) U.S. Pat. No. 4,559,334, discloses a method for synthesis of    cefdinir, wherein the carboxylic acid (IV) activated as the acid    chloride is reacted with 7-amino-3-vinyl-3-cephem-4-carboxylic acid    to give the 7-substituted addendum, which on reaction with thiourea    gives cefdinir.-   b) U.S. Pat. No. 4,409,214 discloses a method identical for    synthesis of cefixime, a structurally similar analogue of cefdinir.-   c) U.S. Pat. No. 5,109,131 describes an advantageous process for    preparation of cephalosporin compounds using    tert-butyl-3-oxobutyrate as an intermediate. The    tert-butyl-3-oxobutyrate is used for preparation of the compound    (IV), which is reacted as such or a reactive derivative thereof is    reacted with a 3-substituted-7-amino cephalosporin compound to form    the 7-substituted cephalosporin addendum, which on reaction with    thiourea gives compounds of formula (II).    -   The reactive derivatives utilised for 7-amidification as        disclosed in U.S. Pat. No. 5,109,131 include acid halides, a        mixed acid anhydride, an active amide or an active ester.-   c) European Patent No. 0 030 294 discloses a method for preparation    of ceftriaxone comprising reaction of    4-bromo-2-methoxyimino-3-oxobutyric acid chloride with    7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic    acid to give the 7-amino addendum, which is cyclized with thiourea    to give ceftriaxone.-   d) European Patent No. 0 842 937 claims a process for preparation of    cefotaxime and ceftriaxone comprising reaction of 7-ACA and    7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic    acid respectively with 4-chloro-2-methoxyimino-3-oxobutyric acid,    activated as 2-mercaptobenzothiazolyl ester, followed by cyclisation    of the intermediates thus obtained with thiourea to give cefotaxime    and ceftriaxone respectively.-   e) U.S. Pat. No. 4,960,766 discloses a method for acylation at the    7-amino position of a 3-substituted cephalosporin derivative by    reaction with compound (IV), which is activated as an acid halide or    as a mixed anhydride, an activated amide or an activated ester in    the presence of dicyclohexylcarbodiimide or an organic or inorganic    base to give the corresponding acylated compound. Formation of the    thiazolyl ring is completed when the acylated compound thus obtained    is reacted with thiourea.-   f) EP Patent No. 0 556 768 describes a method for preparation of    ceftriaxone comprising reaction of    7-amino-3-desacetoxy-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-3-cephem-4-carboxylic    acid with 4-chloro-2-methoxyimino-3-oxobutyric acid, activated as    2-mercaptobenzothiazolyl ester, followed by cyclisation of the    intermediate thus obtained with thiourea to give ceftriaxone . This    patent claims that the abovementioned reaction and subsequent    conversion of ceftriaxone to its disodium hemiheptahydrate salt can    be carried out in one pot using a mixture of acetone and water as    solvent.-   g) U.S. Pat. No. 6,384,215 provides yet another variation, wherein    the compound (Iv) is activated as a    2-mercapto-5-substituted-1,3,4oxadiazole derivative prior to    7-amidification to give compounds of formula (II) after cyclisation    of the intermediate compound with thiourea.-   h) U.S. Pat. No. 6,458,949 discloses a process for preparation of    ceftiofur by reacting silylated    7-amino-3-(2-furylcarbonylthiomethyl)-3-cephem-4-carboxylic acid    with 4-bromo/chloro-2-methoxyimino-3-oxobutyryl acid halide,    followed by cyclization of the compound thus formed with thiourea.-   i) Published U.S. Patent Application No. 2002/0128469 A1 claims an    improved method for preparation of compounds of formula (II),    specially cefotaxime and ceftriaxone comprising reaction of compound    (V, see Scheme-I) with compound (IV) activated as a reactive    derivative to give the corresponding intermediate 7-acylated    compound, the improvement being reaction of the intermediate    7-acylated compound thus obtained is cyclized with silylated    thiourea to form the aminothiazole ring.

Surprisingly, the present inventors have found a novel manner ofactivation of the carboxylic acid of 4-halogeno-2-oxyimino-3-oxobutyricacid of formula (IV), which provides novel reactive derivatives offormula (I).

Thus, it is an object of the present invention to provide novel reactivederivatives of formula I.

Yet further object of the present invention is to provide a simple andcost-effective method for preparation of cephalosporin compounds offormula (II) utilising compounds of formula (I).

SUMMARY OF THE INVENTION

Thus the present invention according to one aspect provides novelcompounds of formula (I)

wherein X is chlorine or bromine;

-   R is hydrogen, C₁₋₄ alkyl group, an easily removable hydroxyl    protective group,-   —CH₂COOR₅, or —C(CH₃)₂COOR₅, wherein-   R₅ is hydrogen, or an easily hydrolysable ester group.

According to another aspect of the present invention there is provided amethod for preparation of compounds of formula (I) comprising reactionof 4-halo-2-oxyimino-3-oxobutyric acid of formula (IV¹),

wherein X and R are as defined hereinbefore with N,N-dimethylformiminiumchloride chlorosulphate of formula (VII)

in an organic solvent at a temperature ranging from −30° C. to −15° C.

According to a further aspect of the present invention there is provideda process for preparation of cephalosporin compounds of formula (II)

wherein R and R₅ are as defined above; R₁ is hydrogen or —OCH₃; R₂ ishydrogen; R₃ is hydrogen, a negative charge or together with the COO⁻group to which R₃ is attached is an ester or an alkali or alkaline earthmetal; R₄ is hydrogen or is a substituent useful in cephalosporinchemistry,

-   the process comprising reaction of compound of formula (I)

wherein X and R are as defined hereinbefore with 7-amino cephalosporanicacid of formula (V),

wherein R₁ is hydrogen or —OCH₃; R₂ is hydrogen; R₃ is hydrogen, anegative charge or together with the COO⁻ group to which R₃ is attachedis an ester, or an alkali or alkaline earth metal, or is a silyl group;R₄ is hydrogen or is a substituent useful in cephalosporin chemistry;and R₆ is hydrogen or a silyl group with the proviso that, when R₃ ishydrogen R₆ is also hydrogen; when R₃ is a silyl group R₆ is also asilyl group; and when R₃ is an ester, or an alkali or alkaline earthmetal R₆ is hydrogen to give7-[(4-halo-2-oxyimino-3-oxobutyramido-3-substituted-3-cephem-4-carboxylicacid of formula (VIII),

wherein X, R, R₁, R₂ and R₄ have the same meanings as definedhereinearlier and R₃ is hydrogen, a negative charge or together with theCOO⁻ group to which R₃ is attached is an ester, or an alkali or alkalineearth metal,

-   followed by cyclisation of compound (VIII) with thiourea to give    compounds of formula (II),

wherein R is hydrogen, C₁₋₄ alkyl group, an easily removable hydroxylprotective group, —CH₂COOR₅, or —C(CH₃)₂COOR₅, wherein R₅ is hydrogen,or an easily hydrolysable ester group; R₁ is hydrogen or —OCH₃; R₂ ishydrogen; R₃ is hydrogen, a negative charge or together with the COO⁻group to which R₃ is attached is an ester or an alkali or alkaline earthmetal; and R₄ is hydrogen or is a substituent useful in cephalosporinchemistry.

The group R₄, which is a substituent useful in cephalosporin chemistryincludes inter alia those substituents which are conventional incephalosporin chemistry and which are useful in pharmaceutically activecephalosporins and thus include unsubstituted and substituted alkyl;unsubstituted and substituted alkenyl; alkyl and an alkenyl substitutedby alkoxy, heterocyclthio, heterocycylcarbonylthio, alkylcarbonyloxy andheterocycyl. Heterocycyl includes 5 or 6 membered heterocycyl includinga bicyclic ring system having 10 to 12 carbon atoms; a heterocycylhaving 1 to 4 hetero atoms, selected from N, O or S.

DETAILED DESCRIPTION OF THE INVENTION

The process for the preparation of the compound of formula II thechemistry of which is summarized in reaction Scheme-II.

The abovementioned aspects of the present invention are illustratedhereinbelow in greater details.

1) Preparation of N,N Dimethyl Formiminium Chloride Chlorosulfite(DFCCS)(VII)

DFCCS (VII) is a known compound and described in the literature, viz. Z.Chem, 6 (4), 148 (1996); J.C.S. Perkin Trans I, 2004-2007 (1972); BullChem. Soc. Jpn., 58, 1063-1064; Adv Org Chem., 9 (2), 5, (1979);Synthetic Reagents, Vol. 4, 388-389; Angew Chem. Internal. Edit., 1(12), 647 (1962); U.S. Pat. Nos. 5,739,346; 5,856,502; 5,945,532 and EPPatent No. 0 791 597.

While DFCCS (VII) prepared by any known process might be used, theinventors have found that best results are obtained when DFCCS (VII) isprepared by the following process.

The preferred process for obtaining the DFCCS (VII) comprises addingsulfuryl chloride to N,N-dimethylformamide at −20° C. The temperature israised to 0° C. at which the solid adduct crystallized out, which isvigorously stirred at for one hour, followed by addition ofdichloromethane to the resulting reaction mixture. The temperature wasraised to 15° C. to 20° C. and at this temperature the solid crystalsmelt, resulting in the formation of an immiscible layer of the desiredadduct, i. e. (VII).

Such mode of preparation of DFCCS (VII) is illustrated in Scheme III.

The DFCCS (VII) adduct thus obtained by the preferred process of theinvention is found to be advantageous in use in the process ofmanufacture of the reactive derivatives of formula I in accordance withthe objective of the invention for the reasons given below:

-   i) Unlike the complex, viz. dimethyl formiminium chloride    chlorosulfite (DFCS) of formula (VI) utilized in the prior art,    DFCCS (VII) used in the process of the present invention remains    stable and does not get converted to the normal Vilsmeier's reagent.    It has been observed that DFCCS (VII) of the present invention is    apparently more stable than DFCS (VI), described in U.S. Pat. No.    5,037,988. In particular, it is found that the thus obtained    DFCCS (VII) used in the process of the invention is distinct from    thionly chloride-DMF adduct, i.e., dimethylformiminium chloride    chlorosulfite (DFCS, VI) known in the art. The melting point of the    latter is 138° C.-140° C. [Helv. Chim. Acta., 62, 1655 (1959)] while    that of DFCCS (VII) is 40° C.-41° C. [Z. Chem., 6(4), 148 (1966)].-   ii) The DFCCS (VII) used in the process of the invention can be    prepared in any solvent such as benzene, toluene, acetonitrile or    dichloromethane, and preferably, in the absence of solvents. This is    advantageous and clearly distinct from the thionly chloride-DMF    adduct, i.e., dimethyl formiminium chloride chlorosulfite (DFCS, VI)    described in U.S. Pat. No. 5,037,988, which cannot be prepared in    solvents such as chloroform or dichloromethane, since these solvents    facilitate complete or partial conversion of dimethyl formiminium    chloride chlorosulfite to normal Vilsmeier's reagent.-   iii) It has been found that sulfuryl chloride-DMF adduct DFCCS of    formula (VII) is more stable than DFCS (VI), made from thionly    chloride and DMF. Thus, when DFCCS (VII) was kept at ambient    temperature for 16 hours and used for further complexion with    compounds of formula (V) for synthesis of the activated ester    required for the final acylation reaction, the drop in yield for the    final antibiotics was about 26% (85% when used fresh and 59% after    storage of DFCCS for 16 hrs.). Similarly when DFCS adduct was kept    at ambient temperature for 16 hrs. and further processed for    synthesis of the final antibiotic, the drop in yield was about 35%    (80% when used fresh and 45% when used after 16 hours). Hence, DFCCS    obtained by the preferred process described above has superior    stability compared to DFCS adduct of formula (VI).

Thus, the use of DFCCS (VII) for synthesis of the compound of formula(I), provides a practical, cost effective and safe method formanufacture of the desired cephalosporin antibiotics of formula (II).

2) Preparation of Novel Compounds of Formula (I):

The reactive compounds of formula (I) is prepared by the reaction of4-halo-2-methoxy imino butyric acid (IV¹) and N,N-dimethyl formiminiumchloride chlorosulfate i.e., DFCCS (VII) as obtained from Scheme-III.

In a typical reaction, DFCCS (VII) is added to 4-halo-2-oxyimino-3-oxobutyric acid (IV¹) in an organic solvent at a temperature of −25° C. to−15° C. and thereafter, the reaction mixture is stirred for two hours ata temperature of 5-10° C. The compound of formula (I) thus obtained canbe stored at low temperature for a period of 3-6 hrs before use in thenext step.

The process is summarized in Scheme-IV.

Any organic solvent can be used in the reaction for formation ofcompounds of formula (I). However, the formation of compound (I) is bestprepared in chlorinated solvents selected from dichloromethane,dichloroethane, and chloroform; aromatic hydrocarbons selected frombenzene and toluene; and nitrile solvents selected from acetonitrile,propionitrile and butyronitrile. However, chlorinated hydrocarbons aremore preferred and among these dichloromethane is the preferred solvent.

The DFCCS (VII) is employed in molar to slightly more than molarproportions to the carboxylic acid compound (IV¹) used. Preferably, themolar ratio of the DFCCS (VII) to the carboxylic acid of formula (IV¹)is between 1.1 to 1.3.

As mentioned hereinearlier, compounds of formula (I) obtained by thereaction summarized in Scheme-IV are relatively stable than other mixedanhydrides and the adduct of the carboxylic acid (IV¹) with DFCS offormula (VI) on storage at low temperatures. The novel compounds offormula (I) can be stored for a time period of 3-6 hours below −20° C.

The compounds of formula (I) exhibit distinct spectral properties asevidenced by their PMR, IR and Mass Spectra.

The PMR spectrum of the novel 4-bromo-2-methoxyimino-3-oxo butyric acidN,N dimethyl formiminium chloride chlorosulfite adduct of formula (I¹)was recorded neat with DMSo-d₆ as external lock at room temperatureusing CH₂Cl₂ as reference. The spectra shows two broad 1H signals at13.4 ppm and 8.2 ppm respectively. Singlets due to —BrCH₂ and —OCH₃ areobserved at 4.3 and 4.1 ppm respectively. The —N(CH₃)₂ signals appearsat 3.2 and 3.1 ppm respectively.

The IR spectrum of the freshly prepared bromo compound (I¹) showssignals at 1784 cm⁻¹ indicating anhydride functionality. After prolongedperiod of time, the signal disappears and a broad signal at 3379 cm⁻¹appears, implying that the anhydride is unstable and gets hydrolysed tothe acid.

The mass spectrum of the bromo compound (I¹) using a non-protic solventat room temperature shows a signal of weak intensity at m/z 397.5 amu inthe +APCI mode of ionization, indicative of the existence of the speciesof formula (I¹).

The PMR, IR and Mass Spectra of the bromo compound (I¹) are reproducedin FIG. 1, FIG. 2 and FIG. 3 respectively.

Of the chloro and bromo compounds of formula (I), the bromo compoundsare preferred for use in synthesis of cephalosporin compounds of formula(II).

The carboxylic acid compounds of formula (IV¹) are known compounds andcan be prepared in high purity and good yield starting from tert-butylacetoacetate as described in U.S. Pat. Nos. 5,095,149 and 5,109,131.

3) Synthesis of Cephalosporin Compounds of Formula (II) Utilizing NovelCompounds of Formula (I).

The novel compounds of formula (I) are useful in the manufacture ofvaluable cephalsosporin antibiotics of formula (II), as per the methodsummarized in Scheme-II. The method provides a practical, cost-eefectiveand safe method for manufacture of the said cephalosporin antibiotics.

Compounds of formula (I) due to their inherent stability on storage arepreferred over the other mixed anhydrides of the carboxylic acid (IV¹)or the adduct of the carboxylic acid (IV¹) with DFCS of formula (VI),which are somewhat less stable.

The process for manufacture of the desired cephalosporin antibiotics offormula (II) according the present invention basically involves thefollowing steps, as summarized in Scheme-II.

-   A. Reaction of compound of formula (I) with the corresponding    7-amino-3-substituted cephalosporonic acid of formula (V) to give    the 7-amino addendum of formula (VII), and-   B. Reaction of the 7-amino addendum of formula (VIII) thus obtained    with thiourea to give the cephalosporin antibiotics of formula (II).

In Step A of the process, the reactive compound (I) is treated with the7-aminocephalosporanic acid of formula (V) in an organic solvent and inthe presence of a base at a temperature ranging from −80° C. to −15° C.,preferably −55° C. to −25° C. yield the 7-amino addendum of formula(VII).

In compounds of formula (V), R₁ is hydrogen or —OCH₃; R₂ is hydrogen; R₃is hydrogen, a negative charge or together with the COO⁻ group to whichR₃ is attached is an ester, or an alkali or alkaline earth metal, or isa silyl group; and R₄ is hydrogen or is a substituent useful incephalosporin chemistry; R₆ is hydrogen or a silyl group with theproviso that, when R₃ is hydrogen R₆ is also hydrogen; when R₃ is asilyl group R₆ is also a silyl group; and when R₃ is an ester, or analkali or alkaline earth metal R₆ is hydrogen

When R₃ is a negative charge, the group R₄ may contain a positivecharge; e.g. in the form of a positively charged amine.

If R₃ together with the COO⁻ group to which it is attached is an estergroup R₃ preferably forms with the COO⁻ group a physiologicallyhydrolysable and acceptable ester, e.g. R₃ is a substituent useful incephalosporin chemistry.

By easily hydrolysable esters of the compounds of formula (II) it is tobe understood compounds of the formula (II) in which the carboxyl groupis present in the form of an ester group which can be easily hydrolysed.Examples of such esters, which can be of the conventional type, are thelower alkyl esters such as methyl, ethyl, tertiary butyl;alkanoyloxyalkyl esters, e.g. the acetoxy methyl, pivaloxymethyl,1-acetoxyethyl, 1-pivaloxyethyl ester; the lower alkoxycarbonyloxyalkylesters, e.g. the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and1-isopropoxycarbonyloxyethyl ester; the alkoxymethyl esters, e.g.methoxy methyl ester, and the lower alkylaminomethyl esters, e.g. theacetamidomethyl esters. Other esters, e.g. the benzyl and cyanomethylesters can also be used.

Alternatively, the compound of formula (V), in which R₃ and R₆ arehydrogen can be reacted with a silylating agent to effect silylation atthe 4-carboxylic acid and the 7-amino position to form the corresponding(bis)-silylated compound of formula (V), wherein R₃ and R₆ are silylgroups, which is then reacted with the reactive compound (I) in anorganic solvent and in the presence of a base at a temperature rangingfrom −80° C. to −15° C., preferably −55° C. to −25° C. to yield the7-amino addendum of formula (VIII).

The silylation of compound (V) can be achieved by conventional waysusing conventional silylating agents such as hexamethyldisilazane,trimethylchlorosilane, bis (trimethyl) silylacetamide etc. The silylatedcompound (V), thus obtained without isolation can be reacted withcompounds of formula (I) to give the 7-amino addendum of formula (VIII).

The basic compounds used as acid scavenging agent to capture HClreleased during silylation include N,N dimethyl aniline, diethyl amine,pyridine, preferably N,N dimethyl aniline.

Any organic solvent can be used in the reaction for formation ofcompounds of formula (VIII). However, the formation of compound (VIII)is best carried out in chlorinated solvents selected fromdichloromethane, dichloroethane, and chloroform; aromatic hydrocarbonsselected from benzene and toluene; nitrile solvents selected fromacetonitrile, propionitrile and butyronitrile; and ether solventsselected from tetrahydrofuran and dioxane. However, chlorinatedhydrocarbons are more preferred and among these dichloromethane is thepreferred solvent.

The compound (I) is employed in molar to slightly more than molarproportions to the cephalosporin compound (V) used. Preferably, themolar ratio of compound (I) to the cephalosporin compound (V) is between1.1 to 2.0 and more preferably between 1.2 to 1.5.

Even though, both the non-silylated cephalosporin compound (V) or thesilylated analogue can be used, because of the ease of reaction and thequality of the product obtained the silylated cephalosporin compound isthe preferred one for reaction with compound (I) in forming the amidebond at the 7-position.

Compound (VIII) can be isolated from the reaction mixture by water andextraction of the product into a suitable organic solvent. The compound(VIII) can thereafter be isolated by evaporation of the solvent andoptional crystallization of the residue thus obtained.

Alternatively, the compound of formula (VIII) need not be isolated and asolution of the same in an organic solvent can be used as such forreaction with thiourea to produce the cephalosporin antibiotics offormula (II).

In Step-B of the process, the compound of formula (II), either isolatedor non-isolated, preferably the latter is reacted with thiourea in anorganic solvent, optionally containing water and in the presence of abase at low to ambient temperature to effect formation of theaminothiazole ring and thereby, affording the cephalosporin antibioticcompounds of formula (II).

In a typical embodiment, a solution of the intermediate compound offormula (VIII) in a suitable organic solvent is treated with a solutionof a mixture of thiourea and a base in water at low to ambienttemperature for 2 to 3 hours at a pH between 5.0 to 6.0 to effectcyclisation of the aminothiazole ring and thereby, produce compounds offormula (II).

Any organic solvent can be used in the reaction for formation ofcompounds of formula (II). However, the formation of compound (II) isbest carried out in chlorinated solvents selected from dichloromethane,dichloroethane, and chloroform; aromatic hydrocarbons selected frombenzene and toluene; nitrile solvents selected from acetonitrile,propionitrile and butyronitrile; and ether solvents selected fromtetrahydrofuran and dioxane. However, chlorinated hydrocarbons andethers are more preferred and among these dichloromethane andtetrahydrofuran are the preferred solvents.

The base used in the reaction can be an organic or inorganic base, thelatter being more preferred since it leads to minimum degradation of thecephalosporin ring. Alkali metal carbonate, such as sodium carbonate,potassium carbonate and lithium carbonate.; alkali metal hydrogencarbonates, such as sodium hydrogen carbonate and potassium carbonate;and alkali metal acetates, such as sodium acetate and potassium acetatecan be used as bases.

The reaction is carried out at temperatures ranging from −5° C. to 40°C., preferably between −10° C. to 30° C.

At the end of the reaction the aqueous phase is separated from theorganic phase and the compounds of formula (II) are isolated by standardmethods known in cephalosporin chemistry.

In the cephalosporin antibiotic compounds of formula (II),

-   R is hydrogen, C₁₋₄ alkyl group, an easily removable hydroxyl    protective group,-   —CH₂COOR₅, or —C(CH₃)₂COOR₅, wherein-   R₅ is hydrogen, or an easily hydrolysable ester group;-   R₁ is hydrogen or —OCH₃;-   R₂ is hydrogen;-   R₃ is hydrogen, a negative charge or together with the COO⁻ group to    which R₃ is attached is an ester or an alkali or alkaline earth    metal;-   R₄ is hydrogen or is a substituent useful in cephalosporin    chemistry.

The group R₄, which is a substituent useful in cephalosporin chemistryincludes inter alia those substituents which are conventional incephalosporin chemistry and which are useful in pharmaceutically activecephalosporins and thus include unsubstituted and substituted alkyl;unsubstituted and substituted alkenyl; alkyl an alkenyl substituted byalkoxy, heterocyclthio, heterocycylcarbonylthio, alkylcarbonyloxy andheterocycyl. Heterocycyl includes 5 or 6 membered heterocycyl includinga bicyclic ring system having 10 to 12 carbon atoms; a heterocycylhaving 1 to 4 hetero atoms, selected from N, O or S;

When R₃ is a negative charge, the group R₄ may contain a positivecharge; e.g. in the form of a positively charged amine.

If R₃ together with the COO⁻ group to which it is attached is an estergroup R₃ preferably forms with the COO⁻ group a physiologicallyhydrolysable and acceptable ester, e.g. R₃ is a substituent useful incephalosporin chemistry.

The term, “easily hydrolysable esters of the compounds of formula (II)”is to be understood as compounds of the formula (II) in which thecarboxyl group to which the group R₃ or R₅ is attached is present in theform of an ester group which can be easily hydrolysed. Examples of suchesters, which can be of the conventional type, are the lower alkylesters such as methyl, ethyl, tertiary butyl; alkanoyloxyalkyl esters,e.g. the acetoxy methyl, pivaloxymethyl, 1-acetoxyethyl, 1-pivaloxyethylester; the lower alkoxycarbonyloxyalkyl esters, e.g. themethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and1-isopropoxycarbonyloxyethyl ester; the alkoxymethyl esters, e.g.methoxy methyl ester, and the lower alkylaminomethyl esters, e.g. theacetamidomethyl esters. Other esters, e.g. the benzyl and cyanomethylesters can also be used.

The term, “an easily removable hydroxyl protective group” is to beunderstood as compounds of formula (II) in which the group R attached tothe oxygen moiety of the oxyimino function are those which protect theoxygen function for further reaction with compound of formula (VII)during the preparation of compound of formula (I) and which can beconveniently be removed after formation of compounds of formula (I).Examples of such hydroxyl protective groups include those of theconventional types routinely used for protection of hydroxyl groups andinclude inter alia trialkyl silyl ethers; trialkylaryl silyl ethers;trialkyl stannyl ethers; trityl; tetrahydropyranyl; alkyl or arylsulfonates such as tosyl, mesyl, besyl etc.; boron or aluminiumcontaining two alkyl groups; (un)substituted benzyl etc.

Compounds of formula (II), wherein the group R₃ is hydrogen can beconverted into their physiologically acceptable salts or esters byreaction of the carboxylic acid compound with suitable reagents thatform the respective salts or esters. For instance, when compound offormula (II) is cefotaxime acid, ceftriaxone acid or ceftiofur acid itcan be converted to the corresponding physiologically more active sodiumsalts by reaction with suitable sodium metal carriers. Similarly, whencompound of formula (II) is cefpodoxime acid or cefditoren acid thesecan be converted into their respective physiologically more activeesters like cefpodoxime proxetil and cefditoren pivoxil by reaction withthe respective ester forming reagents.

Similarly, compounds of formula (II) in which the group R is an easilyremovable hydroxyl protective group can be converted to compounds offormula (II) in which R is hydrogen by removal of the protective groupsby conventional means. For instance, cefdinir, in which the group R ishydrogen can be obtained by removal of any of the abovementionedhydroxyl groups.

Compounds of formula (II), wherein the group R attached to the oximefunction is a group of R₅, such groups can be hydrolysed to a group,wherein R is hydrogen . For instance, cefixime and ceftazidime can beobtained by hydrolysis of the group R₅, which is tertiary butyl or thelike in compounds of formula (II).

Alternatively, compounds of formula (II), wherein the group R₃ is anester group can be converted to compounds wherein R₃ is hydrogen byremoval of the ester function.

Further, the compounds of formula (II) may also be obtained asphysiologically active solvates or hydrates.

It is to be understood all the abovementioned variations of the processform an embodiment of the present invention.

The commercially valuable cephalosporin compounds of formula (II) thatcan be manufactured by the process of this invention include, to name afew:

-   1)    7-[(Z)-2-(2-amninothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic    acid i.e. cefdinir,-   2)    7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino)acetyl]amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)ethenyl-3-cephem-4-carboxylic    acid, i.e. cefditoren and the pivaloyloxymethyl ester i. e.    cefditoren pivoxil,-   3)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrolodino)methyl-3-cephem-4-carboxylate    i.e. cefepime,-   4)    7-[(Z)-2-(2-aminothiazol-4-yl)methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic    acid i.e. cefetamet, and the pivaloyloxymethyl ester i. e. cefetamet    pivoxil,-   5)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic    acid i.e. cefixime,-   6)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[1-methyl-1H-tetrazol-5-yl]thio]methyl]-3-cephem-4-carboxylic    acid i.e. cefmenoxime,-   7)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[[5-carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl]-3-cephem-4-carboxylic    acid i.e. cefodizime,-   8)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,3-dihydro-2-(2-hydroxyethyl)-3-imino-1H-pyrazol-1-yl]methyl]-3-cephem-4-carboxylic    acid i.e. cefoselis,-   9)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]cephalosporanic    acid i.e. cefotaxime,-   10)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[92,3-cyclopenteno-1-pyridinium)methyl]-3-cephem-4-carboxylic    acid i.e. cefpirome,-   11)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate—i.e.    cefpodoxime and the 1-methylethoxycarbonyloxy ether i. e.    cefpodoxime proxetil,-   12)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl-5,6,7-tetrahydroquinolinium-4-carboxylic    acid inner salt i. e. cefquinome,-   13)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethyl)oximinoacetamido}-3-[pyridinium]methyl-3-cephem-4-carboxylacid    acid inner salt i. e. ceftazidime,-   14)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazoyl)-methyl-3-cephem-4-carboxylic    acid i. e. cefteram and the and the pivaloyloxymethyl ester i. e.    cefteram pivoxil,-   15)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic    acid i. e. ceftiofur,-   16)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic    acid i. e. ceftizoxime,-   17)    7-[(Z)-2-(2-amninothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylic    acid i. e. ceftriaxone, and-   18)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(1,2,3-thiadiazol-5-ylthio)methyl]-3-cephem-4-carboxylic    acid i. e. cefuzonam.

The invention can be further illustrated by the following examples,which should not be construed as limiting the scope and spirit of theinvention.

EXAMPLE-1 General method for Preparation of 4-halo-2-oxyimino-3-oxobutyric acid-N,N-dimethyl formiminium chloride chlorosulfate of formula(I)

N,N-dimethyl formamide (1.0 mole) is added to a mixture of sulfurylchloride (1 mole) and of methylene chloride slowly over 30 mins, at atemperature of −20 to −10° C. The mixture is stirred for 2 hrs at 20-22°C. Further methylene chloride is added and the mixture is allowed tosettle down. N,N-dimethyl formiminium chloride chlorosulfate (DFCCS,VII) that remains in the denser organic layer is separated.

The solution of DFCCS (VII) in methylene chloride is added to a solutionof containing 0.75 moles of 4-halo-2-oxyimino-3-oxo-butyric acid offormula (IV¹) in methylene chloride over 30 min at −25 to −15° C. Thereaction mixture was stirred for two hours at 5-10° C. to give the titlecompound (I). i. e. 4-halo-2-oxyimino-3-oxo butyric acid-N,N-dimethylformiminium chloride chlorosulfate of formula (I)

EXAMPLE-2 Preparation of 4-bromo-2(Z)-methoxyimino-3-oxo butyricacid-N,N-dimethyl formiminium chloride chlorosulfate of formula (I)

26.6 g (0.364 moles) of dimethyl formamide was added to a mixture of49.12 g (0.363 moles) of sulfuryl chloride and 50 ml of methylenechloride slowly over 30 mins, at a temperature of −20 to −10° C. Themixture was stirred for 2 hrs at 20-22° C. Further 200 ml of methylenechloride was added and the mixture was allowed to settle down.N,N-dimethyl formiminium chloride chlorosulfate (DFCCS, VII) thatremains in the denser organic layer was separated.

The solution of DFCCS (VII) in methylene chloride was added to asolution of 63.39 g (0.283 moles) of4-bromo-2(Z)-methoxyimino-3-oxo-butyric acid (IV¹) in 800 ml ofmethylene chloride over 30 min at −25 to −15° C. The reaction mixturewas stirred for two hours at 5-10° C. to give the title compound (I) i.e. 4-bromo-2-methoxyimino-3-oxo butyric acid-N,N-dimethyl formiminiumchloride chlorosulfate of formula (I)

¹HNMR (DMSO-d₆): δ, 13.4 (s, 1H), 8.2 (s, 1H), 4.3 (s, —BrCH₂), 4.1 (s,—OCH₃), 3.2 and 3.1 (—N(CH₃)₂.

IR (main bands) in cm⁻¹: 1784

Mass Spectrum: m/z 397.5 amu in the +APCI ionization mode.

EXAMPLE-3 Preparation of Sodium salt of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]cephalosporanicacid (cefotaxime sodium)

Step A: Preparation of 4-bromo-2-methoxyimino-3-oxo butyricacid-N,N-dimethyl formiminium chloride chlorosulfate of formula (I)

The title compound was prepared as described in Example-2.

Step B: Preparation of silylated 7-amino cephalosporanic acid:

81.0 g (0.297 moles) of 7-amino cephalosporanic acid (7-ACA) and 72.3 g(0.448 moles) of hexamethyl disilazane (HMDS) were taken in 600 ml ofmethylene chloride and were refluxed for 3-4 hrs. to give the silylated7-amino cephalosporanic acid.

Step C: Preparation of7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-cephalosporanic acid

The solution of silylated 7-ACA in methylene chloride obtained from StepB was added to the solution of 4-bromo-2-methoxyimino-3-oxo butyricacid-N,N-dimethyl formiminium chloride chlorosulfate in methylenechloride obtained from Step A over a period of 30 mins, at a temperaturemaintained between −80 to −50° C. To the mixture was added 54 g (0.446moles) of dimethylaniline and the progress of the reaction was monitoredby HPLC and after completion of reaction gives the title compound i. e.7-[4-bromo-2 (Z)-methoxyimino-3-oxobutyramido]-cephalosporanic acid.

¹H NMR (DMSO-d₆): δ, 9.43 (1H,d, NHCO), 5.80 (1H,dd, H-7), 5.14 (1H,d,H-6), 5.03, 4.61 (1H each, d, 3-CH₂OCOCH₃), 4.64 (2H,s, BrCH₂—), 4.06(3H, s, —OCH₃), 3.64 (2H, ABq, SCH₂—), 2.02 (3H,s, OCOCH₃)

Step D: Preparation of Cefotaxime

27.2 g (0.3579 moles) of thiourea and 48.6 g (0.3573 moles) of sodiumacetate tri hydrate was dissolved in 250 ml of water. This mixture wasadded to a mixture containing the solution of7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-cephalosporanic acid inmethylene chloride, as obtained in Step C and 490 ml of water over 30mins. The reaction mixture was stirred for 2-3 hrs. The pH of thesolution was adjusted to 5.5 with aqueous sodium bicarbonate.

The aqueous layer was separated and treated with activated carbon andfiltered. To the filtrate 440 ml of tetrahydrofuran (THF) was added andthe pH of the mixture was gradually adjusted to 2.8 with hydrochloricacid. The white solid obtained was filtered and dried at 45° C. for 4hrs under vacuum to give 65.6 g (40.3% yield) of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]cephalosporanicacid (cefotaxime)

Step E: Preparation of Cefotaxime Sodium

20 g (0.0438 moles) of cefotaxime (from Step D) was dissolved in amixture of 40 ml methanol and 20 ml ethyl acetate using triethylamine.To the solution was added a solution of 8.4 g (0.0506 moles) of 2-ethylsodium hexanoate, followed by 250 ml of ethyl acetate. The precipitatedwhite solid was filtered and dried at 45° C. under vacuum to give 18.6 g(88.7% yield) of the sodium salt of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]cephalosporanicacid (cefotaxime sodium) having a purity of 99.0%.

EXAMPLE-4 Preparation of disodium salt of7-[(Z)-2-(2-amninothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid (ceftriaxone sodium)

Step A: Preparation of 4-bromo-2-methoxyimino-3-oxo butyricacid-N,N-dimethyl formiminium chloride chlorosulfate of formula (I)

The title compound was prepared as described in Example-2.

Step B: Preparation of silylated7-amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid

74.0 g (0.458 moles) of hexamethyldisilazane (HMDS) and 10.8 g (0.099moles) of trimethyl chlorosilane (TMCS) was added to a suspension of the100 g (0.2695 moles) of7-amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid and 800 ml of methylene chloride and the mixture refluxed wasrefluxed for 8 hrs to give silylated7-amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid.

Step C: Preparation of7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid (VIII)

The solution of silylated7-amino-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid in methylene chloride as obtained in Step B was added to thesolution of 4-bromo-2-methoxyimino-3-oxo butyric acid-N,N-dimethylformiminium chloride chlorosulfate in methylene chloride, as obtainedfrom Step A over a period of 30 min while maintaining the temperaturebetween −80 to −50° C. To the mixture was added 42.4 g. (0.350 moles) ofdimethylaniline and the progress of the reaction was monitored by HPLC.

After completion of the reaction 800 ml of water and 400 ml of THF wereadded to the reaction mixture at room temperature and agitated. Theorganic layer containing7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid was separated and used as such for the next step.

Step D: Preparation of Ceftriaxone

24.6 g (0.323 moles) of thiourea and 22.6 g (0.269 moles) of sodium bicarbonate was dissolved in 200 ml of water. This mixture was added to amixture containing the solution of7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid in the organic solvent, as obtained from Step C and 600 ml of waterover a period of 30 mins. The reaction mixture was stirred for 60 minsat 5-10° C. The pH of the solution was adjusted to 5.5 with aqueoussodium bicarbonate solution. The reaction was further stirred for 2-3hrs.

The aqueous layer was separated and treated with activated carbon andfiltered. To the filtrate 360 ml of ethyl acetate and 78 ml of IPA wereadded and the pH of the mixture was gradually adjusted to 2.8 byaddition of formic acid. The precipitated white solid of was filteredand dried at 45° C. for 4 hrs under vacuum to give 80.4 g (51.25% yield)of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid (ceftriaxone) having a purity of 90.56%.

Step E: Preparation of Ceftriaxone Sodium

20 g (0.036 moles) of the ceftriaxone, obtained from from Step D wasadded to 120 ml water. To this was added triethylamine for completedissolution of ceftriaxone. The clear solution was treated withactivated carbon and filtered. To the filtrate was added 12.85 g (0.0774moles) of 2-ethyl sodium hexanoate in 800 ml of acetone at 0-5° C. Theprecipitated white solid t was filtered, washed and dried under vacuumat 25° C. to give 18.5 g (77% yield) of the disodium salt of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid (ceftriaxone sodium), having a purity of 94%.

EXAMPLE-5 Preparation of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylicacid (ceftiofur)

Step A: Preparation of 4-bromo-2-methoxyimino-3-oxo butyricacid-N,N-dimethyl formiminium chloride chlorosulfate of formula (I)

The title compound was prepared as described in Example-2.

Step B: Preparation of silylated7-amino-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic acid

30.4 g (0.1883 moles) of hexamethyldisilazane (HMDS) and 20.32 g (0.1873moles) of trimethyl chlorosilane (TMCS) were added to the suspension of80 g (0.2352 moles) of7-amino-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic acidin 800 ml of methylene chloride and the mixture was refluxed for 3 hrsfor complete silylation to give silylated7-amino-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic acid.

Step C: Preparation of7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylicacid

The solution of silylated7-amino-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic acidin methylene chloride as obtained in Step B was added to the solution of4-bromo-2-methoxyimino-3-oxo butyric acid-N,N-dimethyl formiminiumchloride chlorosulfate in methylene chloride, as obtained from Step Aover a period of 30 min while maintaining the temperature between −25 to−15° C. To the mixture was added 38.4 g. (0.173 moles) ofdimethylaniline and the progress of the reaction was monitored by HPLC.

After completion of the reaction 800 ml of water was added to thereaction mixture at room temperature and agitated. The organic layercontaining7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylicacid was separated and used as such for the next step.

¹HNMR (DMSO-d₆): δ, 5.93 (1H,dd, H-7), 5.17 (1H,d, H-6), 4.37(1H,s,—S—CO—), 4.59 (2H,s, BrCH₂—), 4.20 (3H, s, —OCH₃), 3.78 (2H,s,SCH₂—).

IR (main bands) in cm⁻¹: 1780

Step D: Preparation of Ceftiofur

25.0 g (0.3289 moles) of thiourea was dissolved in 160 ml ofdemineralised water. This solution was added to a mixture containing7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylicacid in methylene chloride, as obtained from Step C 240 ml oftetrahydrofuran (THF) over a period of 30 mins. The reaction mixture wasstirred for 2 hrs at 5-10° C. The pH of the solution was adjusted to 5.0with aqueous sodium bicarbonate solution.

The aqueous layer was separated and the pH of the mixture was graduallyadjusted to 3.0. The white solid precipitated was filtered and dried at45° C. for 3 hrs under vacuum to give 1.65 g (21.4% yield) of7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido)-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylicacid (ceftiofur)

EXAMPLE-6

Following the methods described in Examples 1-5 the followingcephalosprorin compounds of formula (II) were prepared by utilizing therequisite starting compounds (I) and (VII). The compounds are:

-   i)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic    acid i.e. cefdinir,-   ii)    7-((Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino)acetyl]amino-3-[(Z)-2-(4methyl-5-thiazolyl)ethenyl-3-cephem-4-carboxylic    acid, i.e. cefditoren and the pivaloyloxymethyl ester i. e.    cefditoren pivoxil,-   iii)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrolodino)methyl-3-cephem-4-carboxylate    i.e. cefepime,-   iv)    7-[(Z)-2-(2-amiothiazol-4-yl)methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic    acid i.e. cefetamet, and the pivaloyloxymethyl ester i. e. cefetamet    pivoxil,-   v)    7-[(Z)-2-(2-aminothiazol]-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem4-carboxylic    acid i.e. cefixime,-   vi)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido)-3-[[1-methyl-1H-tetrazol-5-yl]thio]methyl]-3-cephem-4-carboxylic    acid i.e. cefmenoxime,-   vii)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[[5-carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl-3-3-cephem-4-carboxylic    acid i.e. cefodizime,-   viii)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,3-dihydro-2-(2-hydroxyethyl)-3-imino-1H-pyrazol-1-yl]methyl]-3-cephem-4-carboxylic    acid i.e. cefoselis,-   ix)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[92,3-cyclopenteno-1-pyridinium)methyl]-3-cephem-4-carboxylic    acid i.e. cefpirome,-   x)    7-((Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate—i.e.    cefpodoxime and the 1-methylethoxycarbonyloxy ether i. e.    cefpodoxime proxetil,-   xi)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamndo]-3-[[1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl-5,6,7-tetrahydroquinolinium-4-carboxylic    acid inner salt i. e. cefquinome,-   xii)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethyl)oximinoacetamido}-3-[pyridinium]methyl-3-cephem-4-carboxylacid    acid inner salt i. e. ceftazidime,-   xiii)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazoyl)-methyl-3-cephem-4-carboxylic    acid i. e. cefteram and the and the pivaloyloxymethyl ester i. e.    cefteram pivoxil,-   xiv)    7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic    acid i. e. ceftizoxime, and-   xv)    7-[(Z)-2-(2-amninothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(1,2,3-thiadiazol-5-ylthio)methyl]-3-cephem-4-carboxylic    acid i. e. cefuzonam.

1. A 4-halo-2-oxyimino-3-oxo butyric acid-N,N-dimethyl formiminiumchloride chlorosulfate of formula (I) useful in the preparation ofcephalosporin antibiotics

wherein X is chlorine or bromine; R is hydrogen, C₁₋₄ alkyl group, ahydroxyl protective group selected from trialkyl silyl ethers; trialkylaryl silyl ethers; trialkyl stannyl ethers; trityl; tetrahydropyranyl;alkyl or aryl sulphonates selected from tosyl, mesyl, and besyl; boronor aluminum containig two alkyl groups; unsubstituted benzyl; or—CH₂COOR₅, or —C(CH₃)₂COOR₅; wherein R₅ is hydrogen; or a hydrolysableester group selected from lower alkyl esters; alkanoyloxy alkyl estersselected from acetoxy methyl, pivaloxy methyl, 1-acetoxy ethyl, and1-pivaloxyethyl; lower alkoxycarbonyloxyalkyl esters; alkoxymethylesters; lower alkyl amino methyl; benzyl ester; and cyanomethyl ester.2. A process for preparation of compound of formula (I)

comprising reacting 4-halo-2-oxyimino-3-oxobutyric acid of formula(IV¹),

wherein X is chlorine or bromine; R is hydrogen, C₁₋₄ alkyl group, ahydroxyl protective group selected from trialkyl silyl ethers; trialkylaryl silyl ethers; trialkyl stannyl ethers; trityl; tetrahydropyranyl;alkyl or aryl sulphonates selected from tosyl, mesyl, and besyl; boronor aluminum containig two alkyl groups; unsubstituted benzyl; or—CH₂COOR₅, or —C(CH₃)₂COOR₅; wherein R₅ is hydrogen; or a hydrolysableester group selected from lower alkyl esters; alkanoyloxy alkyl estersselected from acetoxy methyl, pivaloxy methyl, 1-acetoxy ethyl, and1-pivaloxyethyl; lower alkoxycarbonyloxyalkyl esters; alkoxymethylesters; lower alkyl amino methyl; benzyl ester; and cyanomethyl esterwith N,N-dimethylformiminium chloride chlorosulphate of formula (VII)

in an organic solvent at a temperature ranging from −30° C. to −15° C.3. The process according to claim 2, wherein the organic solvent ischlorinated solvents selected from dichloromethane, dichloroethane, andchloroform; aromatic hydrocarbons selected from benzene and toluene; andnitrites selected from acetonitrile, propionitrile and butyronitrile. 4.The process according to claim 2, wherein the molar ratio of compound offormula (VII) to compound of formula (IV¹) is between 1.1 to 1.3.
 5. Aprocess for preparation of a cephalosporin compound of formula (II),

wherein R is hydrogen, C₁₋₄ alkyl group, a hydroxyl protective groupselected from trialkyl silyl ethers; trialkyl aryl silyl ethers;trialkyl stannyl ethers; trityl; tetrahydropyranyl; alkyl or arylsulphonates selected from tosyl, mesyl, and besyl; boron or aluminumcontaining two alkyl groups; unsubstituted benzyl; or —CH₂COOR₅, or—C(CH₃)₂COOR₅; wherein R₅ is hydrogen; or a hydrolysable ester groupselected from lower alkyl esters; alkanoyloxy alkyl esters selected fromacetoxy methyl, pivaloxy methyl, 1-acetoxy ethyl, and 1-pivaloxyethyl;lower alkoxycarbonyloxyalkyl esters; alkoxymethyl esters; lower alkylamino methyl; benzyl ester; and cyanomethyl ester, R₁ is hydrogen orOCH₃; R₂ is hydrogen; R₃ is hydrogen, a negative charge or esterselected from the group of lower alkyl esters; alkanoyloxy alkyl estersselected from acetoxy methyl, pivaloxymethyl, 1-acetoxyethyl, and1-pivaloxyetyl ester; lower alkoxy carbonyloxyalkyl esters selected frommethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and1-isopropoxycarbonyloxy-ethyl ester; alkoxy methyl esters; lower alkylaminomethyl esters; acetamidomethyl ester; benzyl ester; and cyanomethylester, R₄ is hydrogen or is a substituent selected from unsubstitutedand substituted alkyl; and unsubstituted and substituted alkenyl;wherein substituted alkyl andlpr alkenvi beinzsubstituted by alkoxy,heterocyclicthio, heterocycyliccarbonylthio, alkylcarbonyloxy orheterocyclyl, comprising reaction of compound of formula (I)

wherein X is chlorine or bromine; R and R₅ are selected fromcorresponding groups listed for those of formula (II) above with 7-aminocephalosporanic acid of formula (V),

wherein R₁ and R₂ are selected from corresponding groups listed forthose of formula (II) above; R₃ is selected from a group listed for R₃of formula (II) above or a trialkyl silyl group; R₄ is selected from agroup listed for R₄ of formula (II) above; R₆ is hydrogen or a trialkylsily group with the proviso that, when R₃ is hydrogen, R₆ is alsohydrogen; when R₃ is a trialkyl silyl group, R₆ is also a trialkyl silylgroup; and when R₃ is an ester, R₆ is hydrogen to give7-[-(4-halo-2-oxyimino-3-oxobutyramido)-3-substituted-3-cephem-4-carboxylicacid of formula (VIII),

wherein X, R, R₁, R₂, R₃ and R₄ are corresponding groups listed forthose of formula (I) or (II) above followed by cyclisation of compound(VIII) with thiourea.
 6. The process according to claim 5, wherein thereaction of compound (I) and compound (V) to give compound (VIII) iscarried out in an organic solvent and in the presence of a base at atemperature ranging from −80° C. to −15° C.
 7. The process according toclaim 6, wherein the organic solvent is selected from chlorinatedsolvents; aromatic hydrocarbons; nitrile solvents; and ethers.
 8. Theprocess according to claim 6, wherein the base is selected from N,Ndimethyl aniline, diethyl amine, and pyridine.
 9. The process accordingto claim 5, wherein the molar ratio of compound (I) to the cephalosporincompound (V) is between 1.1 to 2.0.
 10. The process according to claim5, wherein the preferred temperature is between −55° C. to −25° C. 11.The process according to claim 5, wherein the reaction of compound(VIII) and thiourea to give the cephalosporin compounds of formula (II)is carried out in a mixture of organic solvent and water and in thepresence of a base at low to ambient temperature.
 12. The processaccording to claim 11, wherein the organic solvent is selected fromchlorinated solvents; aromatic hydrocarbons; nitrile solvents; andethers.
 13. The process according to claim 6, wherein the base isselected from alkali metal carbonates, such as sodium carbonate,potassium carbonate and lithium carbonate; alkali metal hydrogencarbonates, such as sodium hydrogen carbonate and potassium carbonate;and alkali metal acetates, such as sodium acetate and potassium acetate.14. The process according to claim 5, wherein a temperature at which thereaction is carried out is between −5° C. and 40° C.
 15. A processaccording to claim 5, wherein the compound of formula (II) is any one ofi)7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid i.e. cefdinir, ii)7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino)acetyl]amino-3-[(1Z)-2-(4-methyl-5-thiazolyl)ethenyl-3-cephem-4-carboxylicacid, i.e. cefditoren and the pivaloyloxymethyl ester i. e. cefditorenpivoxil, iii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrrolodino)methyl-3-cephem-4-carboxylatei.e. cefepime, iv)7-[(Z)-2-(2-aminothiazol-4-yl)methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylicacid i.e. cefetamet, and the pivaloyloxymethyl ester i. e. cefetametpivoxil, v)7-[(Z)-2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylicacid i.e. cefixime, vi)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[1-methyl-1H-tetrazol-5-yl]thio]methyl]-3-cephem-4-carboxylicacid i.e. cefmenoxime, vii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[[5-carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl]-3-cephem-4-carboxylicacid i.e. cefodizime, viii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,3-dihydro-2-(2-hydroxyethyl)-3-imino-1H-pyrazol-1-yl]methyl]-3-cephem-4-carboxylicacid i.e. cefoselis, ix)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]cephalosporanicacid i.e. cefotaxime, x)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[92,3-cyclopenteno-1-pyridinium)methyl]-3-cephem-4-carboxylicacid i.e. cefpirome, xi)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate—i.e.cefpodoxime and the 1-methylethoxycarbonyloxy ether i. e. cefpodoximeproxetil, xii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl-5,6,7-tetrahydroquinolinium-4-carboxylicacid inner salt i. e. cefquinome, xiii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethyl)oximinoacetamido}-3-[pyridinium]methyl-3-cephem-4-carboxylacidacid inner salt i. e. ceftazidime, xiv)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[2-(5-methyl-1,2,3,4-tetrazoyl)-methyl-3-cephem-4-carboxylicacid i. e. cefteram and the and the pivaloyloxymethyl ester i. e.cefteram pivoxil, xv)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylicacid i. e. ceftiofur, xvi)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid i. e. ceftizoxime, xvii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylicacid i. e. ceftriaxone, and xviii)7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(1,2,3-thiadiazol-5-ylthio)methyl]-3-cephem-4-carboxylicacid i. e. cefuzonam.
 16. The compound of formula (I) according to claim1, wherein R₅ is lower alkyl ester selected from methyl, ethyl, andtertiary butyl; lower alkoxycarbonyloxyalkyl ester selected frommethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, and1-isopropoxycarbonyloxy ethyl; methoxymethyl ester; or acetamidomethylester.
 17. The process according to claim 2, wherein R₅ is lower alkylester selected from methyl, ethyl, and tertiary butyl; loweralkoxycarbonyloxyalkyl ester selected from methoxycarbonyloxymethyl,1-ethoxycarbonyloxyethyl, and 1-isopropoxycarbonyloxy ethyl;methoxymethyl ester; and acetamidomethyl ester.
 18. The processaccording to claim 5, wherein R₅ is lower alkyl ester selected frommethyl, ethyl, and tertiary butyl; lower alkoxycarbonyloxyalkyl esterselected from methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, and1-isopropoxycarbonyloxy ethyl; methoxymethyl ester; and acetamidomethylester.
 19. The process according to claim 5, wherein R₃ is lower alkylester selected from methyl, ethyl and tertiary butyl; and methoxymethylester.
 20. The process according to claim 6, wherein the organic solventis chlorinated solvent selected from dichioromethane, diebioroethane,and chloroform; aromatic hydrocarbon selected from benzene and toluene;nitrile solvent selected from acetonitrile, propionitrile, andbutyronitrile; or ethers selected from tetrahydrofuran and dioxane. 21.The process according to claim 11, wherein the organic solvent ischlorinated solvent selected from dichioromethane, dichloroethane, andchloroform; aromatic hydrocarbon selected from benzene and toluene;nitrile solvent selected from acetonitrile, propionitrile, andbutyronitrile; or ethers selected from tetrahydrofuran and dioxane.